Online Appendix for the following JACC article
TITLE: Recovery of Platelet Function After Discontinuation of Prasugrel or Clopidogrel
Maintenance Dosing in Aspirin-Treated Patients With Stable Coronary Disease: The
Recovery Trial
AUTHORS: Matthew J. Price, MD, James S. Walder, MD, Brian A. Baker, PharmD,
Darell E. Heiselman, DO, Joseph A. Jakubowski, PHD, Douglas K. Logan, MD, Kenneth
J. Winters, MD, Wei Li, PHD, Dominick J. Angiolillo, MD, PHD
APPENDIX
Inclusion criteria: Subjects were eligible to be enrolled if they were ≥18 and <75 years
of age, had stable coronary artery disease (CAD), were receiving aspirin therapy (81 to
325 mg daily) and weighed at least 60 kg. Stable CAD was defined as chronic stable
angina; previous coronary revascularization including PCI or CABG; a prior history of
ACS (≥30 days before screening) but not currently prescribed thienopyridine therapy; or
≥50% luminal obstruction in at least one coronary vessel by coronary angiography.
Exclusion criteria. Subjects were excluded from the trial if they any formal indication
for the use of a thienopyridine; had a contraindication to prasugrel or clopidogrel; had
received a bare metal stent and/or a drug eluting stent within the last 12 months; or had a
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history of New York Heart Association Class III or IV congestive heart failure, systolic
blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg, refractory
ventricular arrhythmias and/or had an implantable defibrillator device. Subjects with a
significant risk of bleeding were also excluded, including those with a contraindication to
treatment with anticoagulant or antiplatelet agents; a history of stroke or transient
ischemic attack; a history or presence of significant bleeding disorders or gastric ulcers;
or abnormal bleeding tendency, thrombocytopenia, thrombocytosis, anemia or
hemoglobin <10 g/dL; and/or major surgery, severe trauma, fracture, or organ biopsy
within 3 months prior to enrollment. Subjects who had received a thienopyridine,
cilostazol, dipyridamole, warfarin, heparin, a glycoprotein IIb/IIIa inhibitor, or a proton
pump inhibitor within the previous 10 days, a fibrinolytic agent within the previous 30
days and those receiving treatment with a nonsteroidal anti-inflammatory drugs or
cyclooxygenase-2 inhibitor exceeding 3 doses per week were also ineligible for the trial.
Participating sites and enrollment. The following centers participated in this trial:
University of Florida Health Sciences Center, Shands-Jacksonville; Black Hills
Cardiology, Rapid City, South Dakota; Medpace Clinical Pharmacology Unit, Cincinnati,
OH; and Scripps Clinic, La Jolla, CA. The protocol was approved by the IRB at all 4
sites, and all 4 sites actively screened patients. The number of patients actually enrolled
per site were: University of Florida Jacksonville – 16; Black Hills Cardiology – 13; Med
Pace Clinical Pharmacology Unit – 27; Scripps Clinic – 0.
Randomization and details of study design. Eligible subjects were randomly assigned
in a 1:1 fashion to 7 days of once-daily treatment with prasugrel 10 mg plus matching
clopidogrel placebo or clopidogrel 75 mg plus matching prasugrel placebo. After
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completion of the 7-day active treatment period, subjects returned at day 1, 3, 5, 6, 7, 9,
11 (or 12) after the last dose of study drug administration for assessment of platelet
function and any adverse events. All subjects continued aspirin therapy at their usual dose
throughout the treatment and washout periods. Study drug was dispensed as double blind,
double dummy, sequentially numbered medication kits. These kits were assembled
following the randomization code issued by an independent biostatistician and were
provided to each site in shipment blocks; sites dispensed kits in sequential order starting
with the lowest numbered kit provided to the site.
Multivariate regression. Stepwise backward multivariate regression of the pooled
treatment groups was performed to determine variables independently associated with the
primary endpoint. Covariates included in the model were treatment assignment, platelet
reactivity IPA 24 hours after study drug discontinuation, age, gender, smoking, diabetes,
hypertension, hyperlipidemia, diagnosis of peripheral arterial disease, and CYP2C19
phenotype.
Sample size calculation. A total of 22 patients in each arm were estimated to provide
90% confidence that the estimate of the number of subjects not returning to baseline was
accurate within ±10% if the true probability is between zero and 15% that the platelet
function of a subject has not returned to baseline by washout Day 7. At least 54 subjects
would provide an adequate sample size in anticipation of a 10% dropout rate. Analyses
were performed with SAS version 9.1 (SAS Institute Inc, Cary, NC).
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